Bone is a dynamic tissue, with a structure comprising a mineral phase associated with an organic matrix. Homeostasis in the adult skeleton requires a balance between bone resorption and bone formation. During resorption, special cells on the bone's surface dissolve bone tissue and create small cavities. During formation, other cells fill the cavities with new bone tissue. An imbalance in the bone remodeling cycle may cause bone loss that eventually leads to bone-related diseases. Cells of an osteoblast lineage (osteoblasts) play a key role in the balance of the bone remodeling cycle by synthesizing and depositing new bone matrix (osteogenesis). Cells of an osteoblast lineage differentiate from mesenchymal stem cells (i.e., mesenchymal precursor cells). Misregulation of the differentiation of mesenchymal precursor cells into osteoblasts may account for several bone related diseases associated with defective osteoblasts (see, e.g., Olsen et al., Ann. Rev. Cell Dev. Biol. 16:191 (2000)), such as, for example, osteoporosis, rickets, osteomalacia, McCune-Albright syndrome, and Paget's disease.
Compositions that stimulating osteogenesis can conveniently be used in therapeutic methods (e.g., oral administration) to treat or prevent these and other disorders. In addition, cells of an osteoblast lineage can conveniently be used in therapeutic methods (e.g., transplantation) to treat or prevent these and other disorders. Methods of stimulating osteogenesis have been described in e.g., U.S. Pat. Nos. 6,369,029 and 5,942,225. It has been difficult, however, to obtain osteoblasts in sufficient numbers to enable effective therapy. For example, U.S. Pat. No. 5,942,225 describes in vitro culture conditions that induce differentiation of human mesenchymal stem cells into cells of an osteogenic lineage using a combination of a steroid (dexamethasone), β-glycerolphosphate and ascorbic acid. However, steroids such as dexamethasone are potent anti-inflammatory drugs that have multiple side-effects. Thus, compositions and methods for appropriate regulation of the proliferation and differentiation of mesenchymal stem cells into cells of an osteoblast lineage has remained elusive.
Thus, there is a need in the art for compositions and methods for inducing differentiation and transdifferentiation of mammalian cells into cells of an osteoblast lineage in vivo and in vitro. There is a particular need for small molecules that can induce in vivo and in vitro differentiation and transdifferentiation of mammalian cells into cells of an osteoblast lineage. The present invention satisfies these and other needs.